Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute of cancer and plays a major role in the morbidity and mortality of breast cancer. Breast cancer metastasizes in a stereotypical pattern, resulting in lesions found in the lymph node, lung, liver and bone marrow. In parallel with hemopoietic stem cell homing, where attention has focused on the role of CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 (SDF-1), recent advances in metastasis research suggest that here too CXCR4/SDF-1 play a critical role in the organ-selective development of breast cancer. Ironically, at present there are no safe therapies that specifically target the metastatic process. The CXCR4/SDF-1 interaction and the resulting cell signaling cascade have emerged as highly relevant targets since they play pleiotropic roles in metastatic progression, especially homing. AMD3100 (Mozobil), the only anti-CXCR4 drug currently in the clinic, has been approved as a stem cell mobilizing agent. However, long-term use can result in fibrosis due to mobilization of mesenchymal stem cells to the lungs and liver. We have developed an intriguing novel class of pyrimidine amines with unique partial anti-CXCR4 activity. The compounds are effective anti- metastatic agents that block homing and recruitment of both cancerous cells and tumor stromal components without mobilizing stem cells or interfering with other functions of CXCR4. This is of particular merit because the interplay between CXCR4 and SDF-1 is critical for normal physiology. The small molecule pyrimidine amines offer a chemical structural foundation for anti-CXCR4 drugs that foretell safer therapeutics with potential for long-term elimination of CXCR4 functions critical for the development of metastatic cancer. The objective is to develop an orally available, safe and efficacious drug against the long-term effects of CXCR4/SDF-1, while demonstrating a pharmacokinetic and specificity profile to merit advancement into human clinical evaluation. The specific aims are: 1) Design and prepare improved anti-metastatic compounds with increasingly diverse chemical scaffolds; 2) Select and progress suitable candidates based on plasma stability, oral bioavailability and in vivo efficacy; and 3) Characterize suitable drug-candidates for advancement to the clinic. PUBLIC HEALTH RELEVANCE: The intended outcome of this proposal is the development of orally available, safe, small molecules that will attenuate breast cancer metastasis in vivo by blocking a specific function of CXCR4 whilst demonstrating a sufficient pharmacokinetic and specificity profile to merit advancement into human clinical evaluation.